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Antiviral Therapies Against Ebola and Other Emerging Viral Diseases Using Existing Medicines That Block Virus Entry [Version 2; Peer Review: 2 Approved]

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Antiviral Therapies Against Ebola and Other Emerging Viral Diseases Using Existing Medicines That Block Virus Entry [Version 2; Peer Review: 2 Approved] F1000Research 2015, 4:30 Last updated: 15 JUN 2021 RESEARCH NOTE Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry [version 2; peer review: 2 approved] Jason Long1, Edward Wright2, Eleonora Molesti3, Nigel Temperton3, Wendy Barclay1 1Section of Virology, St Mary’s Campus, Imperial College London, London, W2 1PG, UK 2Viral Pseudotype Unit (Fitzrovia), Faculty of Science and Technology, University of Westminster, London, W1W 6UW, UK 3Viral Pseudotype Unit, School of Pharmacy, University of Kent, Chatham Maritime, Kent, ME4 4TB, UK v2 First published: 29 Jan 2015, 4:30 Open Peer Review https://doi.org/10.12688/f1000research.6085.1 Latest published: 10 Feb 2015, 4:30 https://doi.org/10.12688/f1000research.6085.2 Reviewer Status Invited Reviewers Abstract Emerging viral diseases pose a threat to the global population as 1 2 intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The version 2 former was the only available intervention when the current (revision) report report unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior 10 Feb 2015 to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus version 1 has turned to re-purposing of existing, licenced medicines that may 29 Jan 2015 limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their 1. Sean Ekins , Collaborative Drug Discovery, ability to inhibit pseudotype viruses (PVs) of two EBOV species, Burlingame, USA Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific 2. Robin A. Weiss, University College London, manner. The commonly used proton pump inhibitors, Omeprazole London, UK and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We Any reports and responses or comments on the propose CQ as a priority candidate to consider for treatment of EBOV. article can be found at the end of the article. Keywords ebola , emerging viral disease, avian influenze , H5N1 , Marburg , chloroquine , omemprazole , esomeprazole This article is included in the Disease Outbreaks gateway. Page 1 of 11 F1000Research 2015, 4:30 Last updated: 15 JUN 2021 Corresponding author: Wendy Barclay ([email protected]) Competing interests: No competing interests were disclosed. Grant information: This work was supported by the grants FLUPIG EU FP7 258084 and BBSRC BB/K002465/1. Copyright: © 2015 Long J et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). How to cite this article: Long J, Wright E, Molesti E et al. Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry [version 2; peer review: 2 approved] F1000Research 2015, 4:30 https://doi.org/10.12688/f1000research.6085.2 First published: 29 Jan 2015, 4:30 https://doi.org/10.12688/f1000research.6085.1 Page 2 of 11 F1000Research 2015, 4:30 Last updated: 15 JUN 2021 protected mice from EBOV infection18,22 and has been previously REVISE D Amendments from Version 1 highlighted as a possible drug to treat EBOV infection11. The units for chloroquine in Table 1 have been corrected from nM to μM. The possible difficulties that may arise with use of re-purposed drugs include unforeseen interactions between virus/drug and host See referee reports causing exacerbation of disease. Therefore it is important to try and understand the mechanism of virus inhibition by such drugs. To this end we re-examined the anti-viral properties of CQ, and show Introduction here that it inhibited the pH-dependent endosomal entry of a pseu- Emerging pathogens such as Ebolaviruses (EBOV), Avian Influ- dotyped virus (PV) bearing EBOV glycoproteins, in the same way enza viruses, Severe Acute Respiratory Syndrome (SARS) virus, as did the potent and specific vacuolar-ATPase (vATPase) inhibitor Middle-East coronavirus (MERS), Chikungunya virus (CHIKV) bafilyomycin A1 (BafA1) (a non-medical laboratory compound). and Dengue virus pose public health challenges that demand We also show that licensed and widely used proton pump inhibitors researchers and governments work together to assess their pan- (PPIs) for treatment of gastric acid reflux, omeprazole (OM) and demic potential and plan mitigating strategies. Of the five species esomeprazole (ESOM), inhibited PV EBOV entry, likely by their of EBOV belonging to the Filoviridae (including Zaire ebolavirus off-target inhibitory activity on endosomal vATPase. (EBOV-Z), Bundibugyo ebolavirus (EBOV-B), Reston ebolavirus, Sudan ebolavirus (EBOV-S) and Tai Forest ebolavirus1), EBOV-Z Methods and EBOV-S are responsible for the majority of outbreaks of Cell culture highly pathogenic haemorrhagic fevers causing high fatality rates2. Human embryonic kidney (293T/17) (ATCC) and Human lung Past outbreaks have been of limited size affecting a local popula- adenocarcinoma epithelial cells (A549) (ATTC) were maintained in tion, however a strain of EBOV-Z is the causative agent of the Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen) supple- current outbreak that began in late 2013 and has since become mented with 10% fetal calf serum (FCS) (Biosera) and 1% Penicillin- an unprecedented and devastating epidemic3,4, resulting in over streptomycin (PS) (Invitrogen). The cell lines were maintained at 20,000 suspected cases, of which those confirmed had a case 37°C in a 5% CO2 atmosphere. fatality rate of around 60% in the afflicted West African countries (http://apps.who.int/gho/data/view.ebola-sitrep.ebola-summary- Compounds 20150107?lang=en and http://www.who.int/csr/disease/ebola/ Chloroquine diphosphate salt (CQ), bafilomycin A1 fromStreptomy - situation-reports/en/). Towards the end of 2014 the trend in case ces griseus (BafA1), omeprazole (OM) and esomeprazole magnesium numbers reversed in Liberia and the epidemic slowed in Sierra hydrate (ESOM) (Sigma) were resuspended as per manufacturer’s Leone and Guinea, but the virus continues to transit in new geo- instructions and aliquots stored at -20°C: CQ was prepared in ster- 5 graphical areas . This epidemic has triggered a significant global ile dH2O; BafA1, OM and ESOM were prepared in sterile DMSO health response relying on primary hygiene and other containment (Sigma). measures that have proved successful in limiting the spread of the virus in previous outbreaks. Given the scale of this outbreak and Plasmid constructs the fear that traditional containment measures may fail to pre- The Bundibugyo ebolavirus (EBOV-B) envelope glycoprotein (GP) vent global spread, several vaccines have been fast-tracked into (FJ217161) coding sequence was synthesised (Bio Basic Inc.) phase I clinical trials6–8 although even if proved efficacious, the and the HA glycoprotein of avian influenza A/turkey/England/50- limited supply of sufficient quantities of vaccine will hinder their 92/91(H5N1) (FLU-H5) was amplified from the HA plasmid of use in the current situation. For disease treatment, patients suf- the H5N1 reverse genetics system23. Both were sub-cloned into fering a haemorrhagic fever have relied on the clinical manage- the pCAGGS expression vector. Expression vectors containing the ment of symptoms (http://www.cdc.gov/vhf/ebola/treatment/). envelope glycoproteins of Zaire Ebolavirus (Mayinga) (EBOV_Z), with a handful of patients in this outbreak receiving experimental Marburg virus (Lake Victoria isolate; MARV) and Gibbon Ape therapies such as ZMapp, TKM-Ebola, brincidofovir and favipira- Leukemia Virus (GALV) (modified to contain the trans-membrane vir (http://www.nature.com/news/ebola-trials-to-start-in-decem- domain of amphotropic murine leukemia virus (A-MLV) envelope ber-1.16342)9–12. Alternatively antibody treatment by transfusion glycoprotein) are described previously24,25. The Renilla luciferase therapy using blood or plasma from Ebola virus survivors has been gene was sub-cloned into pCAGGS expressing vector from a mini- approved11,13–16; although issues with safety and lack of resources genome reporter described previously26. for this method limit its suitability in West Africa today. Having no approved or widely available therapeutics for EBOV, as with Generation of pseudotype viruses many other emerging viral diseases, focus has turned to possible The generation of all lentiviral pseudotype viruses was based on re-purposing of drugs already licensed for other uses by the EMA the methods detailed previously27–29. Briefly, 293T/17 cells were and FDA. Several clinically approved drugs have been identi- seeded into 10cm3 tissue culture plates (Nunc™ Thermo Scien- fied by researchers17–20, including amiodarone, one of the several tific). The HIV gag-pol plasmid, pCMV-Δ8.91 and the firefly luci- cationic amphiphiles found to inhibit filovirus entry which is cur- ferase reporter construct, pCSFLW, were transfected together with rently being trialled in Sierra Leone21. However reservations have either influenza HA, GALV, EBOV or Marburg
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